Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression
Antonio F. Santidrian, … , Takao Yagi, Brunhilde Felding-Habermann
Antonio F. Santidrian, … , Takao Yagi, Brunhilde Felding-Habermann
Published February 15, 2013
Citation Information: J Clin Invest. 2013;123(3):1068-1081. https://doi.org/10.1172/JCI64264.
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Research Article Oncology

Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression

Abstract

Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression.

Authors

Antonio F. Santidrian, Akemi Matsuno-Yagi, Melissa Ritland, Byoung B. Seo, Sarah E. LeBoeuf, Laurie J. Gay, Takao Yagi, Brunhilde Felding-Habermann

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Figure 4

Metastasis inhibition by enhanced complex I activity depends on autophagy.

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Metastasis inhibition by enhanced complex I activity depends on autophag...
(A) ATG5 knockdown (shATG5) inhibited autophagy in MDA-MB-435 and MDA-MB-231 control and Ndi1-expressing cells, as shown by p62 and LC3BI accumulation. Signal quantification of ATG5, p62 signal, and LC3BI/II ratios, measured by infrared imaging (total of detectable bands) and expressed relative to control, is shown below. β-Tubulin served as protein loading control. Lanes were run on the same gel but were noncontiguous (white lines). (B) ATG5 knockdown blocked the antimetastatic effect of Ndi1 in MDA-MB-435 and MDA-MB-231 cells. Lung colonization was measured by ex vivo lung imaging 7 weeks after i.v. injection of 2.5 × 105 tumor cells (n = 8 per group). Boxes denote interquartile range; lines within boxes denote median; whiskers denote minima and maxima. *P < 0.05, nonparametric Mann-Whitney test. (C) ATG5 knockdown enhanced multiorgan metastasis and reversed metastasis inhibition by Ndi1 in MDA-MB-435 cells. Shown is noninvasive bioluminescence imaging of 5 representative mice per group at 7 weeks after tail vein injection of 2.5 × 105 MDA-MB-435 control or Ndi1-expressing cells, with or without ATG5 knockdown.